For many decades Bacillus Calmette–Guérin (BCG) vaccine has served as a weapon for India to tackle the TB menace. However, recent rise in TB cases across India has sparked a debate over the reliability and limitations of this vaccine. The form and mode of action of Mycobacterium tuberculosis has remarkably changed over the years and so has its nuisance value. However, on the other hand, a developing country like India is still heavily relying on age old vaccines like BCG. So, perhaps the time has come to look beyond BCG.
Is there no alternative?
Even the Indian Government is aware of the fact that BCG has its own limitations and a more potent remedy needs to be introduced. India’s revised national TB control programme is the largest TB control programme in the world, placing more than 100,000 patients on treatment every month. However, it seems, even such mammoth efforts are not enough to stop TB’s aggression and hence more advanced vaccines are the need of the hour.
Dr Pradip Shah, Senior Consultant Physician and DNB Teacher, Fortis, Mumbai, opines, “Tuberculosis is one of the most deadly infectious diseases in India. The situation is worsening because of co-infection with HIV and increased occurrence of drug resistance. It is accepted that BCG vaccine protects young children (age, <5 years) against more dangerous extra-pulmonary forms of TB and, thus, is given as a routine vaccination. However, the efficacy of BCG vaccine against pulmonary TB is doubtful. This combination of ineffectiveness and risks of adverse events demands that better vaccines be developed to protect everyone. As of now, we are not ready with an alternative yet.”
Research on TB vaccines
Soumya Swaminathan Director, National Institute for Research in Tuberculosis, Chennai |
Globally, there are various TB vaccine candidates that are in different stages of development. However, till today there is no conclusive outcome from this research.
Swaminathan provides details regarding TB vaccine development. She informs, “There are about 12-14 candidates at different stages of vaccine trial around the globe. So far, results have been disappointing among those that have reached phase 2b. In India, no indigenous TB vaccine candidate has progressed to the stage of human clinical trial, though there is one that is promising in early stage development.”
According to Shah, in India, the only currently licensed vaccine against TB is BCG vaccine, of which >100 million doses are given each year. He stresses that although the BCG vaccine has been in use for 90 years, protection is insufficient; new vaccine candidates are therefore needed.
“In abroad, 12 potential vaccines have gone into clinical trials. Ten are aimed at prevention of TB and, of these, seven are subunit vaccines either as adjuvant or viral-vectored antigens. These vaccines would be boosters of BCG-prime vaccination. Three vaccines are recombinant BCG constructs-possible replacements for BCG. Additional vaccine candidates will enter clinical trials in the near future, including post-exposure vaccines for individuals with latent infection. Although research has focused on injectable vaccines, aerosolised vaccines that are delivered to the deep lung and mimic the natural route of Mycobacterium tuberculosis infection are also being developed, as are oral vaccines (S Rao, K Song, DL Bolton, RL Wilson, JJ Mattapallil, C Andrews, J Sadoff, J Goudsmit, MG Pau, R Seder, PA Kozlowski, GJ Nabel, M Roederer, unpublished data). Both approaches would have the advantage of being inexpensive and easily administered,” says Shah.
| TB Vaccine Pipeline |
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Recombinant BCG vaccines: The first new recombinant BCG TB vaccine to be tested in humans was rBCG30 (developed by Dr. Horowitz’s group at University of California, Los Angeles). The next recombinant BCG vaccine to be tested was VPM1002 (developed by Dr. Kaufman’s group at the Max Planck Institute, Berlin, Germany). Many other recombinant BCG vaccines and recombinant nonreplicating and attenuated TB organisms are in preclinical development. Booster vaccines for BCG- or recombinant BCG-primed infants and for adolescents and adults: Two recombinant proteins combined with advanced adjuvants have been tested in phase I trials in Europe and are currently being tested in studies in Africa. The GSK M72 Aeras-sponsored vaccine is a recombinant fusion protein that has induced protection in long-term nonhuman primate challenge studies and high levels of CD4 T cells in BCG-primed individuals, including HIV-infected individuals with CD4 T cell counts as low as 200 cells/mm3. This vaccine is scheduled for phase IIb efficacy studies in 2010. Two recombinant fusion proteins developed by the Statens Serum Institut, Hybrid-1 and HYVAC4/AERAS-404 (with Sanofi-Pasteur), induce protection in mice and guinea pigs and also induce antigen-specific CD4 T cell responses in humans. Two recombinant nonreplicating viral-vectored TB vaccines have undergone extensive clinical studies and have entered phase IIb proof-of-principle safety and efficacy studies. One of these vaccines, MVA8A/AERAS-485 (Emergent Biosolutions), was developed by Dr. McShane’s group at Oxford University (London, United Kingdom). .On 15 July 2009, a girl became the first infant to receive a new TB vaccine being studied for efficacy in >80 years. In total, 2800 infants in the trial will receive the BCG vaccine at or near birth and a booster at 14–16 weeks of age with eitherMVA85A/ AERAS-485 or placebo. This study has 90 per cent power to detect a 60 per cent decrease in the incidence of clinical TB, compared with placebo. The same vaccine is scheduled to be tested for efficacy in HIV-infected adults with CD4 T cell counts >350 cells/mm3 in 2010. Source: Dr Pradip Shah |
Role of hospitals and pharma companies
Dr Pradip Shah Sr. Consultant Physician & DNB Teacher, Fortis, Mumbai |
Recent findings of MDR-TB cases in the metro cities like Mumbai have made hospitals rework their strategies to handle such cases. Not just hospitals but even pharma companies have to fix their responsibilities as they are the ones who supply medicines/injectibles to hospitals.
“The most important thing is to prevent more MDR-TB from developing by following scientific and rational diagnostic and treatment strategies. All doctors who treat TB should follow standard regimens and recommendations. Pharma companies should not manufacture and market drug combinations that are not recommended. Bioavailability and quality assurance of drugs must be ensured,” says Swaminathan.
While adding to Swaminathan’s suggestions, Shah provides more details on do’s and dont’s for the hospitals and pharma companies. He says, “Of the estimated global total of TB disease cases, an estimated 4.9 per cent cases involve MDR-TB. A vaccine will also help against the spread of drug resistant TB. The new generation of vaccines being developed will protect against drug-resistant forms of the disease, because they are directed against antigens that are not modified by resistance to antibiotics.” Shah adds, “Hospitals should implement policies towards early diagnosis and ethical treatment of MDR cases. There should be proper isolation of such cases and only trained staff and doctors should be involved in treatment. Rational use of antibiotics, low threshold for suspicion and new methods for fast TB cultures and sensitivity patterns should be available at labs. Pharma companies should conduct post market surveillance to know compliance of patients towards and aim at improving it. Single separate drug is better than combination tablets which should be promoted and should be available at reasonable cost.”
Diseases like HIV and TB are difficult to treat. However, due to years of efforts, scientists have managed to make an HIV patient’s life more bearable. In the same manner, though today cases like MDR-TB look deadly, it is to be hoped that scientists across the globe would soon be able to bring TB-related complications under check in the coming years.